Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

This study is ongoing, but not recruiting participants.

Sponsor:

National Cancer Institute (NCI)

ClinicalTrials.gov Identifier:

NCT01767194

First Posted: January 14, 2013

Last Update Posted: December 12, 2017

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
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This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.

Proportion of patients who are responders defined as patients who achieve a >= partial response (PR) per the International Neuroblastoma Response Criteria (INRC) as their best overall response [ Time Frame: Up to 18 weeks ]

Compared between treatment arms using a Fisher's exact test.

Secondary Outcome Measures:

Ability to maintain intended treatment with all agents (irinotecan hydrochloride, temozolomide and the experimental agent) without a dose reduction or going off protocol therapy for toxicity [ Time Frame: Up to 3 years ]

A Fisher's exact test will be used to test for a difference in the proportion of patients who required a dose modification, for temsirolimus versus ch14.18 (dinutuximab). This proportion will be calculated for each treatment group as the number of patients who required a dose modification divided by the total number of patients in that treatment group. Also, the dose modifications for each treatment group will be descriptively summarized.

Occurrence of unacceptable toxicities, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]

The toxicities (grade >= 3) for each treatment group will be descriptively summarized.

Overall survival [ Time Frame: Time of enrollment on the study until the occurrence of the first event or until the time of last contact if no event has occurred, assessed up to 3 years ]

Kaplan-Meier curves will be generated, and curves will be compared using a log-rank test.

Progression-free survival, defined as a relapse, progressive disease, or death attributable to tumor or treatment [ Time Frame: Time of enrollment on the study until the occurrence of the first event or until the time of last contact if no event has occurred, assessed up to 3 years ]

Kaplan-Meier curves will be generated, and curves will be compared using a log-rank test.

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Ages Eligible for Study:

Child, Adult, Senior

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e., > 2 x upper limit of normal [ULN]), at the time of initial diagnosis

For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound; patients must have ONE of the following:

First episode of recurrent disease following completion of aggressive multi-drug frontline therapy

First episode of progressive disease during aggressive multi-drug frontline therapy

Primary resistant/refractory disease (less than partial response by INRC) detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, etc.)

MIBG scan obtained within 3 weeks prior to study entry with positive uptake at a minimum of one site; this site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction

Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma; biopsy is not required for patients who have new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy

Note: Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study

Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age

Patients must have received frontline therapy (including surgery, chemotherapy, autologous stem cell transplant [SCT] +/- MIBG, immunotherapy, radiotherapy, and retinoids) but may NOT have received second line chemotherapy for resistant/refractory, relapsed disease or progressive disease

At least 14 days must have elapsed since completion of myelosuppressive therapy

At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid

No interim time prior to study entry is required following prior radiation therapy (RT) for non-target lesions; however, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response; lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma; palliative radiation is allowed to sites that will not be used to measure response during this study

Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions as long as hematologic and other eligibility criteria have been met

Patients are eligible >= 6 weeks after therapeutic 131I-MIBG provided that all other eligibility criteria are met

Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy; subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads, but no other form of anti-GD2 monoclonal antibody, are eligible

Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study; seven days must have elapsed since administration of a short acting myeloid growth factor

Peripheral absolute neutrophil count (ANC) >= 750/uL

Platelet count >= 75,000/uL (transfusion independent)

Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity

A serum creatinine =< upper limit of normal (ULN) based on age/gender as follows:

Age 1 month to < 6 months: 0.4 for males, 0.4 for females

Age 6 months to < 1 year: 0.5 for males, 0.5 for females

Age 1 to < 2 years: 0.6 for males, 0.6 for females

Age 2 to < 6 years: 0.8 for males, 0.8 for females

Age 6 to < 10 years: 1 for males, 1 for females

Age 10 to < 13 years: 1.2 for males, 1.2 for females

Age 13 to < 16 years: 1.5 for males, 1.4 for females

Age >= 16 years: 1.7 for males, 1.4 for females

Total bilirubin =< 1.5 x ULN for age AND

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L

Adequate central nervous system function defined as:

Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of CNS disease at the time of study enrollment

Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsants

CNS toxicity =< grade 2

Shortening fraction of >= 27% by echocardiogram (ECHO) OR

Ejection fraction >= 50% by ECHO or gated radionuclide study

Adequate coagulation defined as:

Prothrombin time (PT) =< 1.2 x upper limit of normal

Adequate pulmonary function defined as:

No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94% if there is a clinical indication for pulse oximetry; normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung of carbon monoxide [DLCO]) are required if there is a clinical indication for determination; for patients who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT required

Exclusion Criteria:

Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study; based on the established teratogenic potential of alkylating agents, pregnant women will be excluded from this study; female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study; females of childbearing potential must have a negative pregnancy test to be eligible for this study

Patients with elevated catecholamines (i.e., > 2 x ULN) only or bone marrow disease only are NOT eligible for this study

Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment; patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible; the only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions; the use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency

Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment; patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam will be eligible

Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma

Patients with symptoms of congestive heart failure are not eligible

Patients must not have >= grade 2 diarrhea

Patients must not have uncontrolled infection

Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible

Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment are not eligible

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01767194